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Background Maternal smoking during pregnancy was reported to be associated with a reduced risk of type 1 diabetes in the offspring. We investigated whether this association is consistent with a causal interpretation by accounting for familial (shared genetic and environmental) factors using family-based, quasi-experimental designs. Methods We included 2,995,321 children born in Sweden between 1983 and 2014 and followed them for a diagnosis of type 1 diabetes until 2020 through the National Patient, Diabetes and Prescribed Drug Registers. Apart from conducting a traditional cohort study, we performed a nested case–control study (quasi-experiment) comparing children with type 1 diabetes to their age-matched siblings (or cousins). Information on maternal smoking during pregnancy was retrieved from the Swedish Medical Birth Register. Multivariable adjusted Cox proportional hazards regression and conditional logistic regression were used. Results A total of 18,617 children developed type 1 diabetes, with a median age at diagnosis of 9.4 years. The sibling and cousin comparison design included 14,284 and 7988 of these children, respectively. Maternal smoking during pregnancy was associated with a 22% lower risk of offspring type 1 diabetes in the full cohort (hazard ratio 0.78, 95% confidence interval [CI] 0.75–0.82). The corresponding odds ratio was 0.78 (95% CI 0.69–0.88) in the sibling and 0.72 (95% CI 0.66–0.79) in the cousin comparison analysis. Conclusions This nationwide, family-based study provides support for a protective effect of maternal smoking on offspring type 1 diabetes. Mechanistic studies are needed to elucidate the underlying pathways behind this link.

Diabetes is a spectrum of chronic diseases characterized by hyperglycaemia. Theaetiology and pathogenesis differ between types of diabetes, but all can lead tosevere complications. Latent autoimmune diabetes in adults (LADA) is the mostprevalent type of autoimmune diabetes with onset in adulthood, yet risk factorsare largely unknown. Therefore, this thesis was devoted to the study of potentialrisk factors for LADA compared to type 2 diabetes.The Swedish Epidemiological Study of Risk Factors for LADA and type 2 diabetes(ESTRID) constituted the foundation of the four studies in this thesis. ESTRID is acase-control study with incident cases of LADA and type 2 diabetes along withcontrol participants from the general population. Study I, II, and IV werecomplemented with incident cases of LADA and type 2 diabetes as well asdiabetes-free individuals from the Norwegian cohort study HUNT. Study I and IIinvestigated the role of tobacco use and genetic susceptibility for the risk of LADA,using data from ESTRID and HUNT. These analyses were supported by Mendelianrandomization studies based on data from genome-wide association studies. In Study III and IV, data from national and regional health registers were linked toESTRID and HUNT to investigate the association between LADA and priorinfections and antibiotic exposure. Results for LADA were compared to those fortype 2 diabetes in all four studies.We found that smoking increases the risk of LADA, particularly in those withgenetic susceptibility conferred by risk genes associated with autoimmunity, type2 diabetes, or insulin resistance. The increased risk of LADA and type 2 diabetesin smokers seen in the observational data was confirmed in the Mendelianrandomization studies. In contrast, no increased risk of LADA was observed withinfections or antibiotic exposure up to 10 years prior to diagnosis, neither in thosewith high genetic risk nor in those with low-moderate risk. Instead, a reduced riskassociated with antibiotic exposure 6-10 years prior to diagnosis was observed.In conclusion, tobacco use, which is associated with type 2 diabetes and insulinresistance, seems to increase the risk of LADA. Genetic susceptibility plays a roleby aggravating these associations. However, infections and antibiotic exposure,previously linked to type 1 diabetes, were not associated with LADA. Furtherstudies are needed to confirm these results, particularly the finding of a reducedrisk of LADA with prior exposure to antibiotics.

Aims/hypothesis Some studies find an increased risk of type 1 diabetes in children exposed to antibiotics. We investigated if exposure to antibiotics increases the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes. Methods We used data from a Swedish case–control study (Epidemiological Study of Risk Factors for LADA and Type 2 Diabetes [ESTRID]: LADA, n =597; type 2 diabetes, n =2065; control participants matched on participation time, n =2386) and a case–control study nested within the Norwegian Trøndelag Health Study (HUNT) ( n =82/1279/2050). Anatomical Therapeutic Chemical (ATC) codes indicating antibiotic dispensations were retrieved from the Swedish National Prescribed Drug Register and Norwegian Prescription Database. Multivariable adjusted ORs with 95% CIs were estimated by conditional logistic regression and pooled using fixed-effects inverse-variance weighting. Results We observed no increased risk of LADA with exposure to antibiotics up to 1 year (OR pooled 1.15, 95% CI 0.93, 1.41) or 1–5 years (OR pooled 0.98, 95% CI 0.80, 1.20) prior to diagnosis/matching for one or more vs no dispensation of any type of antibiotic. An increased risk was observed for one or more vs no dispensations of narrow-spectrum antibiotics, but not broad-spectrum antibiotics, 6–10 years prior to LADA diagnosis (OR pooled 1.39, 95% CI 1.01, 1.91), which was driven by the Swedish data. There was little evidence of an increased risk of type 2 diabetes associated with antibiotic exposure 1–10 years prior to diagnosis. Conclusions/interpretation We found no evidence that exposure to broad-spectrum antibiotics up to 10 years prior to diagnosis increases the risk of LADA. There was some indication of increased LADA risk with exposure to narrow-spectrum antibiotics, which warrants further investigation. Graphical Abstract

Aims/hypotheses Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. Methods Analyses were based on Swedish case–control data (collected 2010–2019) with incident cases of LADA ( n =593) and type 2 diabetes ( n =2038), and 3036 controls, and Norwegian prospective data (collected 1984–2019) with incident cases of LADA ( n =245) and type 2 diabetes ( n =3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case–control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. Results Smoking (RR pooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. Conclusions/interpretation Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. Data availability Analysis codes are shared through GitHub ( https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA ). Graphical abstract

Background: Mental health disorders can be considered a public health problem and affect approximately one in ten people worldwide. It has profound negative effects on both the individual, the workplace and society. In the Swedish adult working population, diagnoses of mental health disorders is the most common reason for sick leaves among both men and women under the age of 50. Of these, depression and stress reactions are the primary diagnoses. Aim: To examine the relationship between sleep behaviour and depressive symptoms in a sample of working adults. Method: A cross-sectional design with data gathered through the use of actimetry, questionnaires and sleep diaries was employed. Analyses of correlation between sleep variables and depressive symptoms, analysis of variance to detect differences between groups and regression analyses to measure the predictive value of variables have been performed. Results: Depressive symptoms are positively associated with self-rated sleep measures. Self-rated sleepiness showed some explanatory value in predicting depressive symptoms but when adjusting for self-rated stress, sleepiness was no longer significant. Conclusion: Self-rated sleepiness only predicts depressive symptoms to a certain extent. Other factors such as self-rated stress seems to be a stronger indicator of depressive symptoms.